Based on the multitarget strategy, a series of novel clioquinol−1-benzyl-1,2,3,6-tetrahydropyridine hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation in vitro revealed that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE). The optimal compound, 19n, exhibited excellent AChE inhibitory potency (IC₅₀ = 0.11 μM), appropriate metal chelating functions, modulation of AChE- and metal-induced Aβ aggregation, neuroprotection against okadaic acid-induced mitochondrial dysfunction and ROS damage, and interesting properties that reduced p-Tau levels in addition to no toxicity on SH-SY5Y cells observed at a concentration up to 50 μM. Most importantly, compound 19n was more well tolerated (>1200 mg/kg) than donepezil (LD₅₀ = 28.124 mg/kg) in vivo. Moreover, compound 19n demonstrated marked improvements in cognitive and spatial memory in two AD mice models (scopolamine-induced and Aβ_1–42-induced) and suppressed inflammation induced by Aβ_1–42 in the cortex. The multifunctional profiles of compound 19n demonstrate that it deserves further investigation as a promising lead in the development of innovatively multifunctional drugs for Alzheimer's disease.

基于多目标策略，确定了一系列新型氯碘羟喹-1-苄基-1,2,3,6-四氢吡啶杂化物用于阿尔茨海默病 (AD) 的潜在治疗。体外生物学评估表明，这些杂种对乙酰胆碱酯酶 (AChE) 表现出显着的抑制活性。最佳化合物19n表现出优异的 AChE 抑制效力（IC ₅₀  = 0.11 μM）、适当的金属螯合功能、AChE 和金属诱导的 A β的调节聚集、针对冈田酸诱导的线粒体功能障碍和 ROS 损伤的神经保护作用，以及降低 p-Tau 水平的有趣特性，此外在高达 50 μM 的浓度下观察到对 SH-SY5Y 细胞没有毒性。最重要的是，化合物19n在体内比多奈哌齐 (LD ₅₀  = 28.124 mg/kg)具有更好的耐受性 (>1200 mg/kg) 。此外，化合物19n在两种 AD 小鼠模型（东莨菪碱诱导和 A β _{1-42诱导）中表现出认知和空间记忆的显着改善，并抑制了皮质中 A} β _1-42诱导的炎症。化合物19n的多功能概况证明它值得进一步研究，作为开发用于阿尔茨海默氏病的创新多功能药物的有前途的领导。